An inflammatory disease is a generic name for diseases having inflammation as their main damaging factor. Inflammation, which is a biological response of tissue to harmful stimuli, is a lesion with the concurrence of the three events of tissue degradation, circulatory disturbance and fluid exudation, and hypertrophy. Examples of the inflammatory disease include acute and chronic disease, concretely, but are not limited to, edema, dermatitis, allergy, atopy, asthma, conjunctivitis, peridontitis, rhinitis, otitis media, laryngopharyngitis, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, hemorrhoid, gout, ankylosing spondylitis, rheumatic fever, systemic lupus erythematosus, fibromyalgia, psoriatic arthritis, osteoarthritis, rheumatoid arthritis, periarthritis of shoulder, tendonitis, tenosynovitis, myositis, hepatitis, cystitis, nephritis, sjogren's syndrome and multiple sclerosis.
A joint is the location at which two or more bones make contact, typically comprising cartilagenous tissue which functions as a shock absorber. Arthritis is a form of joint disorder that involves inflammation of one or more joints. It is a kind of chronic disease accompanied by the generation of edema, pain and stiffness at the joint affected. In a severe case, arthritis causes disability. Particularly, rheumatoid arthritis is progressive for life in most, causing articular deformity. Often, the absence of effective treatment and the aggregation of the disease result in severe physical disability. The reports of the Center for Disease Control and Prevention (CDC) and the Arthritis Foundation (AF) have it that in the United States, arthritis and other rheumatic conditions were estimated to affect more than 43 million people, corresponding to one fifth of the population, in 1997 and are projected to affect 70 million by 2020, one third of the 2020 population, adding that the number of patients with arthritis will continuously increase with aging of the population. In Korea, it is estimated that as many as 10 million people were affected by arthritis in 2005. There are various forms of arthritis according to its causes although having similar inflammatory symptoms at the joint. The mostly prevalent forms are osteoarthritis (degenerative joint disease) and rheumatoid arthritis. Other arthritis forms include gout and ankylosing spondylitis. Forms of arthritis are classified in Table 1, below.
TABLE 1ClassificationCauses and SymptomsOsteoarthritis(DegenerativeAgingarthritis)Rheumatoid arthritisAbnormality of immune responseGouty arthritisIncreased level and accumulation of uric acid due to abnormal purine metabolismAnkylosing spondylitisCaused by genetic predisposition, or bacterial or viral infection, inflammation at the spineInfectious arthritisArticular tissues infected by pathogensJuvenile idiopathic arthritisThe onset of rheumatoid arthritis before age 16AchillobursitisInflammation around the Archille's tendon
Rheumatoid arthritis is a chronic, systemic inflammatory disease that may affect many tissues and organs, but principally attacks synovial joints. Autoimmunity, that is, an excessive immune response against autologous cells, plays a pivotal role in both chronicity and the progression of rheumatoid arthritis. Inflammation occurs in the cells attacked by the immune system. With time, rheumatoid arthritis nearly always affects multiple joints, most commonly the small joints of the hands, feet and cervical spine, but larger joints like the elbows, hip joints and knees can also be involved. The onset is most frequent in women between the ages of 25 and 50, with physical disability following within 10 years after onset.
After onset, rheumatoid arthritis progresses in concert with the formation of granulation tissue, known as ‘pannus’, at the edges of the synovial lining, which leads to the destruction of articular cartilage, the deformation of the joint, and the weakening of the bones of the joint. The synovial tissue with pannus produces and releases various pro-inflammatory molecules including cytokines, chemokines and the like. Also, the tissue has been recently reported to release a lot of IL-6 and IL-8, known to be involved in the damage and destruction of joints, as well as TNF-α, IL-1β, IL-15 and IL-18. Several cell types have been implicated as major contributors in the patho-physiological process of rheumatoid arthritis, including T cells, B cells, macrophages, synoviocytes and chondrocytes, and they form a division in the joint, producing rheumatoid arthritis inducers that damage articular cartilages and bones.
There are various synthetic compounds that have been developed as medicines for rheumatoid arthritis. However, the FDA ordered the pharmaceutical companies to add a new black box warning to Enbrel, Humira, Remicade and Cimzia about the increased risk of potentially deadly fungal infections. The FDA pointed out that the TNF blockers, although alleviating the pain of the swelling joint, suppress the immune system to make the body vulnerable to various infections, particularly warning the onset of histoplasmosis in people taking the drugs. The FDA has received 240 reports of patients taking TNF blockers who developed histoplasmosis. Among the 240 patients, 45 patients, which correspond to as many as about 20% of those affected, died, including at least 12 who were not diagnosed with histoplasmosis right away. Besides, the Korean Food and Drug Administration (KFDA) announced that a letter, in relation with the death of 130 persons taking a rheumatoid arthritis medicine in Japan, was transmitted to the Korean Medical Association and the Korean Pharmaceutical Association about the side effect of the drug, emphasizing that when taking methotrexate, used as an active ingredient of a medication for arthritis, the patient must be issued with instructions by the attending physicians and pharmacists because the ingredient is likely to cause serious adverse effects such as interstitial pneumonia and bone marrow suppression. Known and unknown, but likely side effects of synthetic medicines for rheumatoid arthritis, such as fungal infections, etc., have recently directed research and development toward natural herbal ingredients that can be safely used in the treatment of rheumatoid arthritis. As a result, several rheumatoid arthritis medicines made of herbal ingredients have been introduced.
Conventional arthritis medicines include non-steroidal inflammatory drugs (NSAIDS), which are expected to bring about pain relief only, adrenocortical hormone agents, which show anti-inflammatoy activity and therapeutic effects, and antirheumatic drugs, which can treat rheumatic arthritis. Representative among the antirheumatic drugs are the immunomodulators such as penicillamine and bucillamine, the immunosuppressants such as cyclosporine, azathioprine, methotrexate and gold salts, and the antimalarial agent hydroxychloroquine, two or more of which are commonly used in combination. For the last five years, many changes have occurred in arthritis medicines. Like TNF blockers and COX-2 inhibitors, drugs which control pain and prevent the generation of many complications have been developed. In scenarios of inflammation, a lot of prostaglandins, a group of lipid compounds, which are inflammatory mediators, are biosynthesized from arachidonic acid, in which cyclooxygenase (COX) is involved. NSAIDS, widely used to treat most inflammatory diseases, function to inhibit the COX enzyme to prevent the biosynthesis of prostaglandins.
Because they employ herbal extracts as their active ingredient, most of the medicines for arthritis are based on natural materials and their accurate pharmaceutical mechanism remains unknown. However, they are actively being developed as oral formulations which are easy to administer and which can be administered for a long period of time. As a natural material, hyaluronic acid, similar to synovial fluid, is injected. As a helper for health functional food, glucosamine is ingested possibly in combination with chondroitin. The development of useful medicines of natural materials may refer to the ancient publications of herbal medicine, such as Tong-Ui-Bo-Gam.
With the great advances in molecular biological technology, the medicinal effects and safety of natural materials have been revealed, and natural medicines are being reviewed from different angles. Now, natural medicines are recognized as special medicines thanks to their advantage of producing no adverse effects even after long-term ingestion. Usually, natural medicines have been developed by utilizing medicinally effective ingredients alone or in combination, and are extracted and isolated from herbs and/or animals which are ingested as food. Having low toxicity compared to synthetic medicines, natural medicines are regarded as being highly safe.
However, natural medicines also have many problems, particularly upon formulation. For example, a dried powder of herbal extract is difficult to handle because it absorbs lots of moisture. Even when it is formulated into a solid oral form, natural medicine is difficult to maintain for a long period of time in terms of morphology and content because it absorbs a lot of moisture when in a formulation.
In the body, various biochemical events account for the onset of inflammation. In response to chemical stimuli, macrophages produce various cytokines and nitric oxide (NO) that play an important role in the inflammatory process. As a result of the inflammatory processes, the supraphysiological concentrations of nitrogen oxide produced by iNOS (inducible nitric oxide synthase) play a major role in the pathobiology of various inflammatory diseases (Kobayashi Y. et al., J Leukoc Biol., 88, pp 1157-62, 2010). In addition, various studies have shown that interleukin-6(IL-6) and interleukin(IL-1β) are a kind of cytokine promoting the inflammatory responses (Punzi L. et al., Crit Rev Clin Lab Sci., 2002, 39(1):63-88), which is known to account for the onset of various inflammatory diseases including rheumatoid arthritis (fang C. H. et al., Rheumatology, 2006, 45(6):703-710), fibromyalgia (Hernandez M. E. et. al., BMC Res. Notes., 2010, 3(1):156), and sjogren's syndrome (Baturone R. et. al., Scand J Rheumatol., 2009, 38(5):386-389). These research results indicate that if it has the function of inhibiting the production of nitric oxide (NO) or cytokines such as IL-6, and IL-1β, a material might be effectively used to prevent and treat various inflammatory diseases.